The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Abstract

Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

Keywords: Chemokines; Neutrophil function; Pre-metastatic niche; Tumor Microenvironment.

Fig. 1

Polarization of neutrophils and macrophages. Two major activation pathways have been described for macrophages and neutrophils. These immune cells can be activated through the classical pathway involving microbial components and T-cell derived factors such as IL-12 and IFNγ, into Type 1 inflammatory cells that combat acute infection. Recent data suggest that IFNβ is also important for the polarization of neutrophils into N1 cells. In the presence of immunosuppressive components such as IL-10, TGFβ, PGE₂, or excessive Th2 responses characterized by IL-13 and IL-4 production, macrophages and neutrophils undergo an “alternative” activation pathway into Type 2 cells, which exhibit immunosuppressive activities. Also, excessive G-CSF and TNFα production may further promote Type 2 activation of neutrophils. Usually, the Type 1 activation prevails under acute inflammation, while Type 2 activation dominates under chronic inflammation, including the tumor microenvironment. Type 2 activation seems to be a negative feedback mechanism that counteracts excessive immune responses

Fig. 2

The crosstalk between cancer cells, neutrophils and other immune cells in the tumor microenvironment. The tumor microenvironment is characterized by a state of chronic inflammation, where tumor cells secrete a range of cytokines and chemokines that recruit and activate neutrophils and other immune cells. Accumulating evidence suggest that neutrophils are essential for mounting an adaptive immune response, as this fails to occur upon depletion of neutrophils. Neutrophils exert both pro-tumor and anti-tumor activities. Through production of ROS, nitric oxide and TRAIL, neutrophils can directly kill the tumor cells. Neutrophils also indirectly prevent tumor growth through eliciting specific anti-tumor CD8⁺ cytotoxic responses. By virtue of their multifunctional tasks, neutrophils may also stimulate tumor growth through secretion of ECM remodeling enzymes and pro-angiogenic factors. As in chronic inflammation, a negative feedback mechanism involved in restricting immune responses, such as the generation of MDSCs, also occurs within the tumor, generating an immunosuppressed environment that antagonizes the anti-tumorigenic activities of neutrophils. The secretion of immunosuppressive factors by the tumor cells themselves further fortifies this immunosuppressed milieu. (TANs Tumor Associated Neutrophils, TAMs Tumor Associated Macrophages)